1. Field
This disclosure is concerned generally with parenteral nutrition and specifically with a novel fat or lipid emulsion suitable for parenteral administration.
2. Prior Art
Lipid emulsions have been widely accepted and used as a means of parenterally administering calories in a highly concentrated form as well as a means of treating or preventing essential fatty acid deficiency during total parenteral nutrition (TPN). It is well known that solutions or emulsions intended for parenteral administration should be physiologically isotonic (i.e. have a pharmaceutically acceptable osmolality) to avoid erythrocyte hemolysis. In the case of aqueous solutions such isotonicity can be assured by the addition of carbohydrates or salts such as sodium chloride. In the case of a fat emulsion, however, salts can be deleterious to emulsion stability. Although the addition of a carbohydrate such as glucose to the aqueous phase does produce a stable, isotonic emulsion, its use can result in undesirable Maillard reactions ("browning") with the free amino groups in phospholipid emulsifiers during thermal sterilization. Because of the above disadvantages, it has been common practice to use glycerol in commercial fat emulsions to assure a pharmaceutically acceptable osmolality without adversely affecting emulsion stability. Such use of glycerol is described, for example, In U.S. Pat. No. 3,109,094 and is used in commercial lipid emulsions (e.g. Intralipid.RTM. I.V. fat emulsion and others).
Although complications are uncommon, there have been numerous reports of acute intravascular hemolysis subsequent to rapid infusion of these glycerol-containing emulsions (Johnstone, A. P., Br. J. Haematol. 50 [2]:376-379 [1982]). In addition, patients on long term TPN receiving intravenous glycerol-containing fat emulsions at proper infusion rates tend to develop low grade anemia which may be due to slight but continuous hemolysis in the peripheral circulation (Marks, L. M., Patel, N., Kurtides, E. S., Am. J. Gastroenterol. 73:490-495 [1980]).
It now appears that all currently marketed fat emulsions are physiologically hypotonic despite the presence of 2.25% w/v glycerol in the formulation. Although a solution of 2.25% glycerol in water has a theoretical (chemical) osmolality of 244 mOsm/l, the effective (biological) osmolality rapidly approaches zero post-infusion due to the high permeability of cell membranes for this solute.
A second problem with glycerol may be the impairment of neutrophil function which has been demonstrated in vitro. This effect may be due to the hypotonicity discussed above and/or to the known ability of glycerol to sequester inorganic phosphate and deplete intracellular ATP (due to rapid formation of glycerol 3-P followed by slow conversion to dihydroxyacetone-P via dehydrogenation) (Burch, H. B. et al., J. Biol. Chem. 257:3676-3679 [1982]). Although the extent to which this occurs in vivo is the subject of current investigation, any impairment of host defenses during TPN would be undesirable.
Finally, glycerol is a poor gluconeogenic substrate in kidney or liver, producing glucose at about 1/3 the rate of lactate or pyruvate (Ross, B. D., Hems, R., and Krebs, H. A., Biochem. J. 102:942-951 [1967]). A new substitute for glycerol in fat emulsions has now been found and details of its use are described below.